RECOMMENDATIONS

Indian Academy of Pediatrics Position Paper on Kawasaki Disease

BHASKAR SHENOY,1 SURJIT SINGH,2 M ZULFIKAR AHMED,3 PRIYANKAR PAL,4 SUMA BALAN,5 VIJAY VISWANATHAN,6
SAGAR BHATTAD,7 ANAND P RAO,8 MAITRI CHAUDHURI,9 DIGANT D SHASTRI10 AND SANTOSH T SOANS11
From Departments of 1Pediatrics, Manipal Hospitals, Bangalore, Karnataka; 2Advanced Pediatric Centre, Post Graduate Institute of
Medical Education and Research (PGIMER), Chandigarh; 3Department of Cardiology, Pushpagiri Medical College, Tiruvalla,
Kerala; 4Department of Pediatric Rheumatology Institute of Child Health, Kolkata, West Bengal; 5Department of Rheumatology,
Amrita Institute of Medical Sciences, Kochi, Kerala; 6Jupiter Hospital, Thane, Maharashtra; 7Aster CMI Hospital, Bangalore,
Karnataka; 8Manipal Hospitals, Indira Gandhi Institute of Child Health, Bangalore, Karnataka; 9Department of Cardiology,
Manipal Hospital, Bangalore, Karnataka; 10Killol Children Hospital, Surat, Gujarat; and 11AJ Institute of Medical Sciences,
Mangalore, Karnataka; India.
Correspondence to: Dr Bhaskar Shenoy, Head, Department of Pediatrics, Manipal Hospitals, Bangalore, Karnataka, India.
bshenoy@gmail.com

Objective: To formulate practice guidelines on diagnosis and management of Kawasaki disease (KD) for Indian children.
Justification: KD is a systemic vasculitis that predominantly affects infants and children less than 5 years of age. Coronary artery
abnormalities (CAA) develop in around 15-25% of untreated children with KD. Coronary artery involvement can lead to long-term
cardiovascular implications such as development of premature coronary artery disease. Diagnosis of KD is essentially clinical based on
recognition of a constellation of characteristic symptoms and signs. Timely diagnosis and initiation of intravenous immunoglobulin (IVIG)
therapy is known to produce five-fold reduction in the incidence of CAA. As there is no confirmatory laboratory test for KD, the
diagnosis may be missed if one is not familiar with the nuances of clinical diagnosis. Process: A committee was formed under the
auspices of Indian Academy of Pediatrics in early 2018 for preparing guidelines on KD in Indian children. A meeting of the consultative
committee was held in Mumbai, and a draft protocol was devised. All members scrutinized the recent publications on the subject and an
attempt was made to arrive at a broad consensus. Published guidelines on the subject were also reviewed. Recommendations:
The diagnosis is clinical and is aided by laboratory and 2D echocardiography. First line of therapy is IVIG, and should be started
expeditiously once the diagnosis is made.
Keywords: Coronary artery abnormalities, Diagnosis, Intravenous Immunoglobulin, Infliximab, Management.

Published online: August 28, 2020; PII: S097475591600188

K
awasaki Disease (KD) is an acute febrile
illness that commonly affects children below
5 years of age. Classified under pre-
dominantly medium vasculitides, it has a
predilection to involve coronary arteries. Ever since the
first report by Dr. Tomisaku Kawasaki from Japan in 1967
[1], the disease has been increasingly reported world-wide.
KD has become one of the leading causes of acquired heart
disease among children in many developed countries.
Incidence of KD has been increasing significantly
over the last decade, even in India, possibly due to a
combination of an actual increase in incidence and also due
to heightened awareness amongst the pediatricians [2]. A
high index of suspicion supported with relevant
laboratory tests and imaging (2D echocardiogram) is often
needed in establishing the diagnosis. Though various
consensus guidelines are available for diagnosis and
management of KD, a nation-wide consensus for a
resource constrained setting like ours is the need of the
hour.
PROCESS
A National Consultative Group was constituted under the
auspices of Indian Academy of Pediatrics (IAP) in March,
2018 for preparing the guidelines on KD in Indian children.
This group of experts consisted of pediatricians, pediatric
rheumatologists and pediatric cardiologists known for
their expertise and experience in treating KD across the
country. A meeting of the consultative committee was held
in Mumbai in March, 2018 to discuss the scientific
contents. The members reviewed the available literature
and discussed various aspects of forming the guidelines
and a draft protocol was devised. This was reviewed by all
the members and a final draft recommendation was formed
through a virtual meeting. The draft recommendations
formulated by the group were circulated among the
members and a consensus document was finalized.
DIAGNOSIS
We have two established criteria that could be used as a
guide for diagnosis of KD – The American Heart

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Association (AHA) criteria [1] and the Japanese criteria [7].
AHA criteria have been discussed in this document and are
detailed in Box I.
Clinical Features
Thorough history and assessment of clinical findings play
a major role in the diagnosis, as there are no specific tests.
Principal Clinical Findings
Diagnosis of KD is usually made on the basis of fever for ≥5
days along with the history/presence of ≥4 out of the 5 key
clinical features. Diagnosis is made as per features given in
Box I but the presence of classic clinical presentation or
coronary artery abnormality, the diagnosis of KD can be
made in less than 5 days.
Fever: The most common manifestation is fever, which is
often high grade and remittent type. If untreated, fever
continues for 1-3 weeks and resolves spontaneously by 3
to 4 weeks, mean duration of fever being 11 days.
Conjunctival injection: Bilateral, painless and non-
exudative conjunctival injection with peri-limbal sparing
usually begins in first few days after fever onset, seen in 80-
90% cases. Slit lamp examination might reveal anterior
uveitis during the first week of fever. Purulent
conjunctivitis should suggest alternate diagnosis.
Oral changes: Bleeding, crusting, dryness, erythema and
fissuring of lips are common mucosal changes noted in KD
patients. Oral mucosal and pharyngeal erythema can also
be seen. Erythema of tongue along with the presence of
prominent papillae results in a strawberry tongue
appearance.
Box I Classical Diagnostic Clinical Criteria of
Kawasaki Disease by the American Heart
Association [1]
Fever persisting >/=5 days
History/Presence of >/=4 principal features
• Changes in extremities (pedal edema in acute
phase, periungual peeling in sub acute phase
• Polymorphous rash
• Bilateral bulbar conjunctival injection without
exudates
• Changes in lips and oral cavity
• Cervical lymphadenopathy (>1.5 cms diameter)
Exclusion of other diseases with similar findings.
All manifestations may not be present at the same time
in a given child, as they are often transient. However, a
thorough history is likely to elicit findings which maybe
presently absent.
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Cervical lymphadenopathy: Cervical adenopathy is
usually non-specific and the least common clinical finding.
Unilateral enlargement of a cervical node >1.5 cm diameter
in the anterior triangle of neck may be noted. Occasionally
the lymph node mimics suppurative lymphadenitis and
may be associated with retropharyngeal/parapharyngeal
edema (phlegmon) mimicking a retropharyngeal abscess on
MRI. But presence of associated clinical features of KD
helps in clinching the diagnosis.
Rash: A maculopapular erythematous rash that begins in
trunk, later extending to extremities and face, is usually seen
by 5 days of onset of the illness. Sometimes it resembles a
scarlatiniform, erythroderma, erythema multiforme, or
urticaria like rash. Bullous, vesicular or petechial rashes are
usually not seen and suggests an alternate diagnosis.
Extremity changes: During the acute phase, erythema of
palms and soles along with edema and induration of hands
and feet may be seen. Desquamation of fingers and toes
usually occurs 10-20 days after the onset of fever and
typically starts in the periungual region. It may extend to
involve the entire palm and sole.
Other Clinical Findings
Perianal or perineal desquamation is typically seen
during the acute phase of KD, as early as day 6 of fever and
is a useful clinical pointer.
Reactivation of BCG scar: Erythema and induration can
occur at the site of BCG scar. Though noted in a small
proportion of children with KD, it is virtually patho-
gnomonic when other findings are missing [1].
Nervous system: Irritability is a common finding especially
marked in infants. It is usually out of proportion to the
degree of fever and thought to be a manifestation of aseptic
meningitis. Profound sensorineural hearing loss may be
present. Facial palsy, though rare, has been well
documented. Prolonged unexplained fever with extreme
irritability may be the only clinical manifestation in many
infants below 6 months of age without any of the principal
clinical signs of KD.
Gastrointestinal system: Diarrhea, vomiting, pain
abdomen, hepatitis, pancreatitis and gallbladder hydrops
can be present.
Genitourinary system: Urethritis/meatitis is a common
feature in the acute phase presenting as sterile pyuria. Less
common features are hydrocele and phimosis.
Musculoskeletal system: Pain and swelling of inter-
phalangeal joints may occur during the acute phase.
Arthritis of large joints (knees and ankles) usually occur
during the convalescent phase and is seen in 10-15% of
cases.
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Respiratory system: Tachypnea, dyspnea, and cough may
rarely be seen. Chest radiograph may reveal peri-bronchial
or interstitial infiltrates.
Cardiovascular: Pericarditis, myocarditis, valvular dys-
function, congestive heart failure, and peripheral gang-rene
are the cardiovascular manifestations of KD.
About 5% of children may present with cardio-vascular
collapse and shock that may be difficult to differentiate
from toxic shock [8,9]. High index of suspicion and presence
of accessory clinical features helps in clinching the
diagnosis. KD shock is readily responsive to IVIg which
helps in differentiating from a viral myocarditis.
Beau lines: Transverse grooves in the nails can be noted 1-
2 months after the onset of illness indicating a catabolic
process in the preceding weeks.
Definitions used in KD diagnosis are provided in Box
II, and approach to a child with suspected incomplete KD is
shown in Fig. 1.
Laboratory Tests
Diagnosis of KD is about pattern recognition with impetus
being on a good history and detailed physical examination.
Laboratory tests are non-specific and are only supportive
and laboratory findings vary with the course of illness.
Hemoglobin: Mild to moderate normocytic, normo-chromic
anemia is common.
Leucocyte count: Leukocytosis is usually seen in acute
phase of illness with neutrophilic predominance.
Platelet count: Thrombocytosis is one of the significant
lab findings in KD. Platelet count starts rising after first
week, reaching a peak in the third week and normalizing by
4-6 weeks. Thrombocytopenia is uncommon but can occur
Fever ≥5 days and less than 4 classical
features of Kawasaki disease
↓ ↓
CRP 3 mg/dL and/or ESR ≥40 mm/hour
↓
Echocardiogram
Positive*
Treat ← Elevated ALT level
(*Positive echocardiogram: refer to the section on echocardiography; CRP: C reactive protein; ESR: erythrocyte sedimentation rate;
ALT: alanine transaminase; WBC: White blood cell count).
Fig. 1 Evaluation of suspected incomplete Kawasaki disease (Source AHA 2017) [1].
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Box II Definitions Used in Diagnosis of Kawasaki
Disease
Complete KD: Patients with fever of at least 5-day
duration with presence/history of 4 or more of the 5
principal clinical findings are labelled as typical or
classic KD.
Incomplete KD: Presence of fever with less than 4
out of the 5 principal clinical criteria with compatible
laboratory or echocardiography findings suggest
incomplete KD. Often seen in infants <6 months
and children >6 years of age, the incomplete clinical
picture often delays the diagnosis. Approach to a
child with suspected incomplete KD is shown
(Fig. 1).
Atypical KD: Patients who along with the usual
clinical features of KD also have few unusual
clinical manifestations like pulmonary involvement,
renal impairment are diagnosed to have atypical
KD.
The terms atypical KD and incomplete KD are inter-
changeably used, but recent consensus is to use atypical
KD in patients who have unusual clinical features and
complications of KD.
in first week. Thrombocytopenia is a risk factor for
development of CAA and may be a marker of incipient
macrophage activation syndrome [10,11].
Acute phase reactants like Erythrocyte sedimentation rate
(ESR) and C-reactive protein (CRP) are almost always
elevated in KD. IVIG therapy by itself can cause an
elevation in ESR leading to doubts in the mind of the
treating physician. Hence, CRP is more useful to assess
response to treatment with IVIG. Macrophage activation
syndrome which can rarely complicate KD should be
suspected in patients with severe clinical disease
Unexplained fever in infants ≥7 days
At least 3 of the following:
Platelet count ≥450,000/mm3
Negative → Anemia for age
Albumin ≤3 g/dL
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associated with minimally elevated ESR and markedly
elevated CRP. It might be prudent to look for an elevated
serum ferritin to confirm this suspicion.
Serum transaminases: Mild to moderate elevation is seen
in around 50% of patients.
Serum albumin: Hypoalbuminemia is often noted in the
acute phase suggesting severe inflammatory process.
Sterile pyuria (>0 cells/high power field with sterile
cultures): This is due to urethritis and sometimes be
mistaken for urinary tract infection in infants.
Procalcitonin levels are usually normal, but elevated
levels are associated with increased risk of IVIg resistance
and CAA [12]. Serum Pro-BNP (Pro-brain natriuretic
peptide) and N terminal Pro BNP (NT-ProBNP) levels are
elevated in KD and can serve as useful biomarkers in
distinguishing incomplete KD and closely mimicking febrile
illnesses. Serum levels of NT-Pro-BNP > 225 pg/mL can
assist in the diagnosis of KD (suggesting myocardial
dysfunction) (86.5% sensitivity and 94.8% specificity) [13].
ECG may reveal evidence of myocarditis and conduction
disturbances. An ultrasound of the abdomen may show
hepatomegaly, hepatosplenomegaly, acalculous
cholecystitis (gall bladder hydrops).
Echocardiography
Echocardiography is the imaging modality of choice for
diagnosis, risk stratification, treatment planning, prog-
nostication and follow-up of any suspected or confirmed
KD. KD is a clinical diagnosis and role of echocardio-
graphy is to only confirm/exclude cardiac involvement,
especially coronary arteritis. Thus, treatment of KD should
not be withheld for local non-availability of pediatric
cardiologist. Simultaneously, the pediatrician should refer
to the pediatric cardiologist if pyrexia of unknown origin
lasts longer than 7 days.
Objectives of Echocardiography in KD
• To confirm the diagnosis in case of suspected
incomplete KD, though a normal echocardiogram does
not exclude the diagnosis.
• To quantify coronary changes in proven KD.
• To look for other cardiac complications like myocarditis
and cardiovascular collapse (5%), valvular regurgi-
tation (e.g., mitral regurgitation), pericardial effusion
[1,8,9].
• To assess response to therapy by serial echocardio-
graphy (regression, persistence or progression of
aneurysm, myocarditis and valvular dysfunction).
• To look for myocardial ischemia secondary to coronary
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involvement, usually seen in giant/large aneurysms.
• Rarely rupture of aneurysm with cardiac tamponade
especially in acute phase with rapid enlargement of
aneurysm.
• Prognostication and counselling of family.
• Long term follow-up of KD with persistent CAA.
Echocardiographic Changes in KD
The cardiac involvement in KD can be grouped into (a)
early changes (b) subacute changes (c) late changes.
(a) Early changes (1st week of fever): Coronary changes
are uncommon in the first week. The important clues are
myocarditis (prevalence 50-70%), pericarditis, small
pericardial effusion and transient mild to moderate mitral
regurgitation (23-27%). We recommend use of advanced
echo modalities like myocardial performance index and
tissue doppler to document myocarditis in addition to
standard parameters like ejection fraction (EF) and
fractional shortening (FS) [14,15].
7% of children with KD in US present with cardio-
vascular collapse (KD shock syndrome). The unique
features of KD myocarditis are (1) it presents early (2)
precedes coronary arteritis, (3) transient and resolves
earlier than other causes of myocarditis as inflammation
and myocardial edema subside. In doubtful cases, serum
NT pro BNP may be used as a surrogate marker, although it
is nonspecific and cut off values yet to be clearly defined
[13,16,17]. We reiterate that normal coronaries in the first
week do not exclude KD.
(b) Subacute changes (after 1st week of fever): The
highlight of this phase is detection of coronary
involvement and its aftermath.
Some tips and clues for successful echo in KD child are
given in Box III. The coronary involvement as per z score
classification is as follows [1]: No involvement: z score
always <2; and Dilatation only: 2 to < 2.5. Aneurysms as
per size: Small CAA: ≥2.5 to <5 mm; Medium CAA: ≥5 to
<10 mm and absolute dimension >8 mm; Large/Giant CAA:
≥10 mm or absolute dimension ≥8 mm. Aneurysms as per
shape: saccular or fusiform.
The Heart Beyond the Coronaries
Apart from early phase, echo during the subacute and long
term phases should focus also on:
• Aortic root dilatation and aortopathy
• Cardiac valves: Late onset regurgitation is attributed
to fixed damage to valve apparatus by the inflammatory
mechanism.
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Box III Tips for Successful Echocardiography in a
Child With Suspected Kawasaki Disease
• Sedation should be used, as these children
(especially infantile KD) are extremely irritable
and toxic.
• To accurately identify coronary arteries, we
recommend use of highest frequency echo
transducers (10-12 Hz).
• The main coronary segments to be visualized
are: left main coronary artery (LMCA) bifurcating
into left anterior descending artery (LAD) and
circumflex (Cx), right coronary artery (origin, mid
and distal segments).
• The luminal diameter from inner edge to edge
is taken in zoomed mode. Please note all
measurements are to be compared with the
child's body surface area. Weight and
especially height are to be considered while
interpreting coronary sizes. Z Scores are then
calculated as per BSA.
• Myocardial function: Both global and regional wall
motion abnormalities (RWMA) perfused by particular
coronary territories are to be reported. Abnormal
RWMA is a clue of myocardial ischemia and prompts
further analysis by CT or direct coronary angiography.
How Frequently Should One Repeat Echo in a
Child with KD?
• At diagnosis.
• Uncomplicated patients: 1-2 weeks and also 4-6 weeks
after treatment. This is because dilatation is unusual
beyond 6 weeks. Normal coronaries may be discharged
from cardiology care after 12 months but the medical
records should permanently mention the diagnosis of
KD.
• For significant and evolving coronary abnormalities:
At least twice per week till luminal dimensions stabilize
and we should look specifically for thrombus. After
that at 2 weeks, 4-6 weeks, 3 months and then every 6-
12 months till parameters normalize.
• To detect coronary artery thrombosis it may be
reasonable to perform echocardiography for patients
with thrombus at diagnosis, expanding large or giant
aneurysms twice per week while dimensions are
expanding rapidly and at least once weekly in the first 45
days of illness, and then monthly until the third month
after illness onset, as failure to escalate
thromboprophylaxis is a primary cause of morbidity and
mortality.
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Long Term Cardiac Assessment in KD
Long-term status is when the patient is stable after the
acute illness and the coronary artery luminal dimensions are
not increasing or progressing (usually within 15 to 45
days).
• 5% of acute coronary syndrome in US has been
attributed to missed KD in childhood [18,19].
• Normal coronaries at initial presentation usually have
no long term sequelae.
• Small or moderate aneurysms usually demonstrate
normalization of luminal dimensions, infrequently
stenosis may happen. Development of late aneurysms
especially with coexistent stenosis is also reported
especially with repeat KD or suboptimal initial
treatment.
• Coronary artery events (thrombosis, stenosis,
intervention, MI, death) occurred in 1% of those with
an aneurysm Z score <10 and an absolute dimension <8
mm, in 29% of those with a Z score ≥10 but an absolute
dimension <8 mm, and in 48% of those with both a Z
score ≥10 and an absolute dimension ≥8 mm [20, 21].
• Subclinical functional impairment (fibrofatty changes,
necrotic core and calcification) of these coronaries have
been observed with advent of intravascular ultrasound
(IVUS) and optical coherence tomography (OCT).
Interestingly wall thickening was found more in those
coronaries where aneurysms normalized on
longitudinal follow up. PET scan shows increased
uptake in these areas [22-24]. Clinically these translate
to impaired myocardial flow and reduced response to
traditional coronary vasodilators like nitroglycerin.
This poses a risk to myocardial infarction in KD
survivors.
Limitations of echocardiography: Despite its primary
position as a diagnostic modality for KD, echocardio-
graphy has some limitation:
• Abnormal coronaries are seen in only 20- 25% of KD.
Hence, a normal echo does not preclude KD [1].
• Coronary artery aneurysms usually appear after 1st
week. It must be repeated in all KD patients after 2 and 6
weeks [1].
• Cardiac sequelae in classical and incomplete KD are
same. So, cardiologist has to be more meticulous while
imaging suspected atypical KD because diagnosis
rests on 2 D echo and laboratory findings.
Role of Other Cardiovascular Imaging Modalities
Acute phase: Echocardiography is the best modality.
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Medium and long term phase: As the child grows,
transthoracic echocardiography may not be able to
visualize especially the distal coronary segments.
Apparent normalization of coronary diameters may also be
due to intimal calcification and fibrofatty changes. So, use
of CT coronary angiography, PET scanning, cardiac MRI
and documenting inducible myocardial ischemia
(Dobutamine stress echocardio-graphy, stress thallium
scan, PET) to assess myocar-dial function and ischemia in
older children, adolescents and adult survivors is
recommended. Exercise TMT alone is not sufficient to
detect these changes. If any of these are positive, direct
coronary angiography as a planner for subsequent
angioplasty or bypass surgery is to be done.
Differential Diagnosis
Infections: Bacterial (streptococcal, leptospirosis,
rickettsia), Viral (measles, adenovirus, Epstein Barr virus).
Toxin related: Staphylococcal scalded skin syndrome,
toxic epidermal necrolysis.
Inflammatory: Systemic juvenile idiopathic arthritis.
Drug hypersensitivity: Steven-Johnson syndrome, drug
reaction with eosinophilia and systemic symptoms
(DRESS), mercury hypersensitivity.
Gastrointestinal features like paralytic ileus, gall
bladder hydrops, greenish diarrhea, jaundice and raised
transaminases may mimic other gastrointestinal infections
or surgical conditions. Sterile pyuria and CSF pleocytosis
can masquerade as urinary tract infection or aseptic
meningitis.
A fever that does not appear to respond to
antimicrobials should always raise the consideration of
alternate pathologies like inflammatory or vasculitic illness
like KD.
TREATMENT
Acute Kawasaki Disease
The goal of treatment is to control the acute inflammation
and prevent long term coronary sequelae. IVIG and high-
dose aspirin are the cornerstones in the management of
KD, although the role of high-dose aspirin in the acute
stages is debatable. Treatment should be initiated promptly
and must not be delayed awaiting echocardiography, when
the clinical features are suggestive of KD.
Single dose of IVIG 2g/kg administered over 12-24
hours should be given within 10 days of illness, preferably
in the first 7 days [1]. Timely administration of IVIG reduces
the development of CAAs from 15-25 to 3-5%, and the risk
of giant aneurysms to 1% [1].
IVIG should be considered even in patients with >10
days of illness with persistent fever, systemic inflammation
evidenced by elevated ESR or CRP (>3.0 mg/L), or presence
of CAAs. IVIG may not be needed in patients who had

Table I Differential Diagnoses of Kawasaki Disease (KD) and Differentiating Features

KD Scarlet fever Measles SJS TSS SJIA
Strawberry tongue Present Present Absent Absent Absent Absent
Red eyes Present (non- Absent Exudative Absent Exudative Absent
exudative) conjunctivitis conjunctivitis
Red lips Present Absent Absent Absent Absent Absent
Response to antibiotics Does not Brisk response NR NR NR NR
respond in 48 h
Peeling Perineal and Generalized NR NR Generalized NR
periungual
Follicular tonsillitis Usually absent May be present NR NR NR NR
Edema of extremities Present Absent Absent Absent Absent Absent
Koplik spots Absent NR Present NR NR NR
Oral ulcers Absent NR NR Present NR NR
Hepatosplenomegaly Absent Absent NR NR NR Present
Hypotension /renal impairment Absent NR NR NR Present NR
Leukocyte counts Elevated May be elevated Normal NR NR Elevated
ESR and C-reactive protein Elevated May be normal NR NR NR Elevated
NR: Non-relevant; SJS: Steven Johnson syndrome; TSS: Toxic shock syndrome; SJIA: Systemic onset juvenile idiopathic arthritis; KD:
Kawasaki disease; ESR: Erythrocyte sedimentation rate.

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resolution of fever with normal inflammatory parameters and
normal echocardiography findings [25].
Dose of aspirin used in the acute stages is 30-50 mg/kg/
day in 3-4 divided doses, that is continued until the patient
is afebrile for 48 hours. The dose of aspirin (ASA) is
reduced to 3-5 mg/kg/day and continued for 6-8 weeks and
stopped if CAAs are not detected in the 6th week
echocardiography. The anti-platelet dose of aspirin is
continued in patients who have persistent CAAs until the
normalization of coronary artery dimensions. Patients on
long-term aspirin need influenza vaccination yearly to
reduce the risk of Reye syndrome.
Multiple studies have come up recently, demons-
trating the beneficial use of corticosteroids along with IVIG
in children predicted to have an increased risk of CAAs and
IVIG resistance [3]. Addition of glucocorti-coids
(prednisolone) to IVIg has been shown to reduce the risk of
CAAs, duration of fever, and inflammation in Japanese
children who are at a high risk for resistance to IVIG
therapy. A recently published Cochrane database systemic
review has even suggested that a long course of steroids
along with IVIG should be considered in all children with
KD until further evidence are available [26].
Recommended use of steroids in KD: Oral prednisolone (2
mg/kg/day) to be initiated with IVIG and gradually tapered
over 15 days after normalization of CRP levels.
In IVIG responsive patients, fever usually subsides by
36-48 hours along with decrease in inflammatory
parameters. Patients with recurrent KD, defined as a repeat
episode of KD after complete resolution of the first episode,
should receive standard therapy with IVIG and ASA.
Anticoagulation in Kawasaki disease is indicated in the
following situations: (a) Giant aneurysm, multiple or
complex aneurysms, presence of thrombus; (b) associated
stenosis; and (c) peripheral gangrene.
It is prudent to initiate with LMW heparin followed by
oral warfarin to maintain INR of 2-2.5. However in view of
the difficulty of maintaining the target INR in children on
oral anticoagulants, one may consider continuing long term
thromboprophylaxis with LMW heparin only after proper
parental counselling.
For arterial thrombosis/peripheral gangrene-
thrombolytic therapy has been tried in addition to
anticoagulation.
Treatment of incomplete KD: Incomplete forms should be
treated in the same manner as complete KD.
Resistant Kawasaki Disease
Children who have persistence or recurrence of fever 36
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hours after the end of IVIG infusion are considered to be
IVIG resistant [1]. Around 10 to 20% of patients are IVIG
resistant [27]. Prolonged fever and unresponsiveness to
the first dose of IVIG are significant risk factors for CAAs.
Risk scores for predicting non response to IVIG: Egami [28],
Sano [29] and Kobayashi [30] scoring systems are some of
the scoring systems that have been shown to predict IVIG
resistance.
There is no established consensus on the
pharmacologic treatment of refractory KD. Various
therapeutic options available -
IVIG retreatment: Many experts recommend retreatment
with second dose of IVIG 2g/kg. Rate of refractoriness to
the second dose IVIG is around 22-49% [31].
Corticosteroids: Furukawa, et al. [32] compared the
effectiveness of second dose IVIG and IV prednisolone in
patients with IVIG resistant KD. They found that incidence
of CAA and treatment failure were similar between 2
groups; however, the steroid group had a faster
defervescence of fever and improvement in inflammatory
markers [32]. The AHA recommends that a short duration of
high-dose glucocorticoids could be a reasonable treatment
option in patients with IVIG resistant KD [1].
Infliximab: Infliximab is a chimeric monoclonal anti TNF-α
antibody. Dose is 5 mg/kg given intravenously over 2
hours. Studies have not demonstrated superiority of
infliximab over others in IVIG-resistant KD in terms of
coronary artery outcomes though fever and other
constitutional features resolve well. The AHA recommends
the use of infliximab as a substitute for a 2nd dose IVIG or
steroids in resistant KD [33,34].
Cyclosporine: Cyclosporine inhibits lymphocyte
activation by blocking the NFAT-calcineurin pathway that
is thought to influence disease susceptibility and
development of CAAs in KD [35]. The AHA recommends
the use of cyclosporine as a possible third or fourth-line
therapy in patients with KD.
Plasma exchange: Used rarely for children who have
active inflammation despite multiple doses of IVIG,
corticosteroids, and infliximab.
Cytotoxic agents: Cyclophosphamide is used to treat
other severe vasculitides, but the risks of cytotoxic agents
limits its use.
Statins: Statins, hydroxymethylglutaryl coenzyme A-
reductase inhibitors, have been shown to reduce
cholesterol levels as well as improve surrogate markers of
atherosclerosis and cardiovascular disease. Huang, et al.
[36] reported a beneficial effect of short-term (3 months)
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INDIAN ACADEMY OF PEDIATRICS
statin treatment (simvastatin, 10 mg/day as a single dose at
bed time) in KD patients complicated with CAL. Chronic
vascular inflammation is also significantly improved, as
well as endothelial dysfunction, with no adverse effects.
However, long-term and randomized control trials are
needed before further conclusions can be made.
It has been recently reported that atorvastatin is able to
inhibit critical steps (T cell activation and proliferation,
production of the pro-inflammatory cytokine TNF-α, and
up-regulation of matrix metalloproteinase-9 and an
elastolytic protease) known to be important in the
development of coronary aneurysms in an animal model
of KD, suggesting that statins may have therapeutic
benefits in KD patients [37]. Taken together, statins may
be beneficial as an adjuvant therapy in KD patients with
CAL.
Management of Cardiovascular Sequelae
Coronary artery aneurysm is a potential serious cardiac
complication of KD. With giant coronary artery aneurysm,
there is increased risk of thrombosis, stenosis, ischemia,
infarction and death [38,39]. The goals of long-term
management are to prevent thrombosis and myo-cardial
ischemia while maintaining optimal cardiovascular health
[39].
Medical therapy for myocardial protection: α- blockers
used are carvedilol, metoprolol or bisoprolol. They
decrease the risk of myocardial infarction and death by
reducing myocardial oxygen demand. ACE inhibitors or
ARBs also protect against myocardial infarction and
death. Statins in addition to their cholesterol lowering
action have other pleiotropic effects in inflammation,
endothelial dysfunction, oxidative stress, platelet
aggregation, coagulation and fibrinolysis, which make
them useful in the management of KD [37].
Thromboprophylaxis: Antiplatelet drugs like aspirin are
commonly used in KD. In giant aneurysm or large distal
aneurysms, a dual antiplatelet treatment with aspirin and
clopidogrel is preferred. Anticoagulation with warfarin to
achieve a target INR of 2-3 is used. LMWH is equally
effective to warfarin, used in young children in whom
dosing with warfarin is difficult [1].
Surgical management: is rarely required in pediatric age
group. It includes percutaneous coronary intervention or
coronary artery bypass grafting [38].
Macrophage activation syndrome (MAS) is a dreaded
complication that may rarely occur characterized by
persistent fever, pancytopenia, liver dysfunction, hepato-
splenomegaly, hyper-ferritinemia, hypofibrino-genemia,
elevated serum lactate dehydrogenase, and hypertrigly-
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POSITION PAPER ON KAWASAKI DISEASE
ceridemia. Prompt treatment with pulse methylpredni-
solone along with IVIg may result in favorable outcome [1].
KD should be diagnosed and treated by primary care
pediatricians. However, involvement of a pediatric rheu-
matologist is required in some circumstances:
• Incomplete/atypical KD,
• KD in infancy,
• presence of CAL at diagnosis,
• IVIG-resistant KD,
• KD shock syndrome, and
• suspicion of a macrophage activation syndrome.
CONCLUSION
Kawasaki disease is the most common cause of acquired
heart disease in children in the developed world. It is being
increasingly recognized and treated in various parts of our
country. Pediatricians must be aware of the varied
manifestations of KD. Early diagnosis and prompt treatment
can result in better outcomes.
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